Please describe the research questions of your lab.
I lead a research program in translational metabolomics in critical care. Collectively, our work is aimed at using metabolomics (the measurement of small molecules in a single biological sample) to further understanding of the mechanisms that drive the pathogenesis of critical illnesses and underlie disease endotypes. We use pharmacometabolomics (the application of metabolomics to predict drug response) to differentiate patients who respond favorably to an intervention from those who do not and are applying principles of metabolomics to better understand mechanisms that contribute to adverse drug events.
Broadly, the research questions we are addressing include identification of the metabolic processes that underpin and explain:
1) endotypes of sepsis and the acute respiratory distress syndrome (ARDS). These are clinically characterized but much is unknown about the physiologic and biologic processes that differentiate these groups of patients. By gaining knowledge in these domains and the contribution metabolism makes to the heterogeneity of these illnesses, we are more likely to identify opportunities for targeted drug therapy and other interventions.
2) sepsis-induced organ dysfunction and failure. Mitochondrial dysfunction may contribute to sepsis-induced organ dysfunction and failure. We are interested in understanding why some patients appear to have more flexible or agile metabolism that may enable them to circumvent a number of consequences of sepsis including organ dysfunction/failure and persistent critical illness.
3) prediction of therapeutic response. We have leveraged data from clinical trials of L-carnitine in septic shock to more fully understand the metabolic processes that contribute to its therapeutic benefit. More recently, in an ancillary study and secondary analysis of a phase II clinical trial, we found that participants with serum acetylcarnitine concentrations >30µM may be more likely to derive a therapeutic benefit from L-carnitine. This represents an example of how pharmacometabolomics can be used to develop enrichment strategies for the design of clinical trials.
What genetics/genomics techniques do you utilize in your lab?
We are a metabolomics laboratory for which we use analytical techniques such as nuclear magnetic resonance (NMR) and liquid-chromatography (LC)-mass spectroscopy (MS) to measure metabolites in a number of different types of biofluids including whole blood and urine. An advantage of the metabolome is it that reflects activity of the genome, transcriptome, and proteome and gives a read of the physiologic landscape which makes it ideal for biomarker and drug target discovery.
Describe a key technique/assay/instrument utilized in your lab, and what novel insights does it bring to your research question?
In addition to our NMR and LC-MS assays, we have optimized an assay for the measurement of short-chain fatty acids (SCFA) in non-fecal samples. This is helping us understand the systemic influence of SCFA levels on the pathogenesis of sepsis and ARDS. By measuring serial arterial and venous blood concentrations of SCFA and other metabolites we can monitor changes in vital organ metabolism (e.g., the lungs!). This approach permits the study of the metabolome-microbiome interface. For this, we have been employing our newly developed swine models of sepsis and ARDS. While we have a number of key techniques that aid in the accomplishment our research goals, the most important and the ones that makes it all possible, are the collaborators I have at Michigan and through the relationships I have developed with ATS colleagues.
At what point in your life did you decide you wanted to be a scientist/physician?
Early, as an undergraduate chemistry student. I loved being in the laboratory. My passion for science continued and my interest in biomedical research emerged as I started pharmacy school. I spent my spare time in a pharmacology laboratory assisting with the development of an isolated-buffer perfused rabbit heart model. There I gained an appreciation for the heterogeneity of drug response and the importance and value of using experimental models to untangle clinically important problems.
In your opinion, what is one of the most important discoveries in the field of respiratory illness/disease/function that was dependent on genomics or similar techniques?
From a therapeutics perspective, my pick is the advancements that have been achieved using genomics to understand cystic fibrosis and the development of not just novel but live-changing therapeutics.
Briefly describe your favorite publication involving genomics/omics that you were involved with in general-audience terms.
I would have to say our “proof of principle” paper that demonstrated the utility MRI and metabolic NMR for the detection of lung inflammation (Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L152-61. doi: 10.1152/ajplung.00515.2007. Epub 2008 Apr 25. PMID: 18441091). Working in a mouse model, we obtained temporal MRI images of the lungs during the formation and resolution of cytokine-induced lung inflammation. We also measured lung tissue metabolites at two time points and assessed lung histopathology at experiment termination. We found that the MRI detection of lung edema and NMR-measured changes in energy metabolism were both sensitive to temporal changes in lung injury as measured by BAL albumin-to-protein ratio and histological endpoints.
It was an early example of how metabolomics reflects physiological changes in the host and how complementary techniques can used to understand metabolic processes that contribute to a clinical phenotype. This paper represented my transition into metabolomics and launched much of my metabolomics-related work. Since then, we have conducted studies in humans including a pharmacometabolomics study of L-carnitine in septic shock (doi: 10.1513/AnnalsATS.201409-415OC).
What is your favorite aspect of ATS?
The annual “in person” meeting- which I greatly missed in both 2020 and 2021. The annual ATS meeting affords me the opportunity to meet new people and re-engage with collaborators and colleagues that I do not get to see that often. The meeting is also a catalyst for forging new collaborations and sparking new ideas. Through the Genetics and Genomics section and the ATS Workgroup on Metabolomics and Proteomics I was fortunate to meet a number of ATS members that I continue to work with. These collaborations led to a successful metabolomics and proteomics workshop (supported by an NIH R13) and the publishing of the symposium as an official ATS Workshop report.
How could your research assist scientists and clinicians in other assemblies at ATS?
In my view, metabolomics is not optimal as a stand-alone science. It is greatly enriched by other systems biology sciences (e.g., proteomics, genomics) as well as information from the microbiome and other physiologic and clinical details. Although my primary research focus is on critical care, I collaborate with a number of ATS members in other assemblies. For example, I have collaborated with a number of investigators working on chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Several of these members are from other ATS assemblies.
Would you be open to collaborations with GG and/or non-GG scientists and clinicians? Do you have any potential lab openings currently or in the near future?
I am always open to new collaborations with GG and/or non-GG scientists and clinicians. At present, I do not have any lab openings but that may change in 2022.
Please include your email address or lab website to share with potential collaborators!
